APOE-ε4 links CD8+ T cell infiltration to white matter inflammation in Alzheimer’s disease

Abstract Background APOE-ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and has been linked to immune dysregulation, yet its impact on adaptive immunity remains poorly defined. Methods We profiled adaptive immune changes in human APOE-ε3 and APOE-ε4 knock-in (KI) mice using mass cytometry (CyTOF). To assess brain infiltration, we performed ex vivo transendothelial migration assays and validated findings in brain tissue from APOE KI mice and human AD donors using immunohistochemistry. Results APOE-ε4 was associated with a shift in peripheral immune composition toward memory CD8⁺ T cells with impaired ex vivo activation capacity. Functionally, CD8⁺ T cells from APOE-ε4 KI mice showed increased migration across brain microvascular endothelium via CD11a/ICAM-1 interactions. In human APOE-ε4ε4 AD tissue, CD8⁺ T cells with tissue-resident and exhaustion marker expression infiltrated the white matter, which correlated with HLA-DR⁺ and myelin-laden microglia. Conclusions APOE-ε4 drives changes in adaptive immune cell states and enhances CD8⁺ T cell trafficking across the blood–brain barrier. These findings link peripheral CD8⁺ T cell dysregulation to white matter neuroimmune alterations in AD and identify the CD11a/ICAM-1 adhesion axis as a candidate mechanism underlying this process in APOE-ε4 carriers.